Lung cancer is the most common cancer in the world and tobacco smoking is the major risk factor, accounting for about 90% of the cases. Early detection of premalignant lesions or tumors appears to be an efficient approach for reducing the morbidity and mortality from lung cancer because the survival of early stage lung cancer patients is much better than that of patients with advanced cancers. Although tobacco smoking accounts for the majority of lung cancer, approximately 10% of patients with lung cancer in the United States are victims of exposure to second hand tobacco smoke. In addition, the individuals who have quit smoking (ex- smokers) are another group of people who are also at risk for developing lung cancer. Therefore, identifying novel mechanism based preventive approaches for tobacco smoke-induced lung cancer through the use of dietary substances is a highly desirable goal. The activation of mammalian targets of rapamycin (mTOR) signaling and cyclooxygenase (COX)-2 has long been associated with malignant transformation and has emerged as important cancer chemopreventive/chemotherapeutic targets. Retinoids are required for proper differentiation of lung and upper airway epithelium, and loss of expression of retinoic acid receptor (RAR)- is characteristic of many lung cancers. Based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis, pomegranate fruit extract (PFE) was found to contain anthocyanins (such as delphinidin, cyanidin and pelargonidin) and several hydrolysable tannins (such as punicalin, pedunculagin, punicalagin, gallagic and ellagic acid esters of glucose). We have recently reported that PFE caused inhibition of prosurvival signaling pathways in human lung carcinoma A549 cells and inhibited tumor growth in athymic nude mice and A/J mice. Capitalizing on our compelling studies in cell-culture and in-vivo work, through this proposal, it is hypothesized that PFE will inhibit/delay lung tumor progression of adenomas to adenocarcinomas by suppressing mTOR signaling and expression of COX-2 as well as induction of retinoic acid receptor (RAR)- in lungs of A/J mice. Studies will also be conducted to examine the effect of PFE on these targets in human non-small cell lung cancer cells. HEALTH RELEVANCE: Verification of this hypothesis could be extremely useful to establish the usefulness of PFE for the development of novel therapeutic approaches in improving the quality of life of early stage lung cancer patients and individuals who are ex- smokers.